| Chromium (CrIII) is a beneficial micronutrient and has shown significant anti-diabetic activity. However, inorganic chromium compounds have some drawbacks, including low absorption rate and toxicity. Organic chromium complexes, including chromium picolinate, chromium nicotinate and chromium yeast, and inorganic chromium compounds such as chromium trichloride, have been widely used as functional food ingredients and nutritional supplements. To date, chromium picolinate is the organic complex most commonly utilized as a dietary supplement. Chromium picolinate can result in DNA toxicity, cytotoxicity and reproductive toxicity. Therefore, characterizing the anti-hyperglycemic activity of novel and non-toxic organic chromium complexes is an important issue. Chromium malate is a type of organic chromium compound that has been synthesized in our research group. Cr3+was chelated by L-malic acid, which was selected as the natural ligand. Its chemical formula and molecular weight are Cr2(C4H4O5)35H2O and 590.18 g/mol, respectively. Our previous study showed that chromium malate improved the regulation of blood glucose in Institute of Cancer Research (ICR) mice, with alloxan-induced diabetes. Chromium malate does not cause oxidative DNA damage, LD50>5.0 g/kg bm and was tested as non-toxic in acute and subacute toxicity studies. Therefore, chromium malate has potential for application as a functional food and nutrient supplement. However, no studies on anti-hyperglycemic activity, mechanism and safety evaluation of chromium malate exist. In the present study, chromium malate was given to type 2 diabetic rats, and their glycometabolism, learning and memory ability, related enzyme, dose-response relationship and mechanisms were evaluated. Chromium malate was used to evaluate pharmacokinetics and bioavailability after oral and intravenous administration to rats. Chromium malate was given to female and male rats and its 90-day oral toxicity, reproductive toxicity, chronic toxicity, glycometabolism, learning and memory ability and related enzymes were evaluated. This study will provide a basis for research and development of a safe, non-toxic functional food ingredient and nutritional supplement.The main content of study are given below:(1) Models of type 2 diabetic (T2D) rats were developed using high sugar and high fat diet and injected with STZ. The type 2 diabetic rats were treated with chromium malate, the glycometabolism, glycometabolism-related enzyme levels and lipid metabolism, learning and memory ability and related enzymes were evaluated. Our results showed that fasting blood glucose (FBG) level had a significant downward trend when compared with the chromium picolinate group and chromium trichloride group. The serum insulin level, insulin resistance index and C-peptide level in the high dose group had a significant downward trend when compared with the model, chromium picolinate and chromium trichloride groups. The hepatic glycogen, glucose-6-phosphate dehydrogenase and glucokinase levels in the high dose group were significantly higher than those of the model, chromium picolinate and chromium trichloride groups. Chromium malate in a high dose group can significantly increase high density lipoprotein cholesterol level while decreasing the total cholesterol, low density lipoprotein cholesterol and triglyceride levels when compared with chromium picolinate and chromium trichloride groups. Chromium malate can significantly improve the learning and memory ability of T2D rats and the expression of related enzymes (superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and acetylcholinesterase (AChE)), as well as the gram bacteria of intestinal flora. Therefore, it can be concluded that chromium malate can be used to improve the glycometabolism, learning and memory ability and gram bacteria of intestinal flora in T2D rats.(2) Effects of chromium malate on anti-hyperglycemic activity and serum metal elements in type 2 diabetic rats:A dose-response study. The results showed that the anti-hyperglycemic activity increased with administration of chromium malate in a dose-dependent manner. The dose-response equation was:Y=-0.4701X+20.914 (R2=0.9847, Y is FBG, X is Cr concentration) between the dose of 7.5-20.8 μg Cr/kg bm. The minimum and maximum effective dose of chromium malate were 7.5 and 13.8μg Cr/kg bm, respectively. The ED50 was 13.8μg Cr/kg bm. The range of effective dose of chromium malate was 7.5-20.8 μg Cr/kg bm. Chromium malate (17.5 and 20.0μg Cr/kg bm) significantly increased the serum calcium, magnesium, iron, copper and zinc levels in type 2 diabetes rats. Therefore, it can be concluded that chromium malate can improve serum elements disorder caused by T2D.(3) The present study was designed to identify the pharmacokinetics and bioavailability of chromium malate in sprague-dawley (SD) rats. The results indicated that chromium malate in vivo pharmacokinetic parametersis fit with two-compartment model. Chromium malate can significantly prolong MRT and increase AUC (male) compared with chromium picolinate. The relative bioavailability of chromium malate was significantly higher than that of chromium picolinate. And the relative bioavailability of chromium malate in male rats was significantly higher than that of female rats. The relative bioavailability of chromium malate was 111.80±1.81% and 113.28±1.72% in female and male rats, respectively. Administration of chromium malate had no obvious effect on the absorption of calcium, magnesium, iron, copper and zinc in normal rats. Therefore, it can be concluded that the Cr supplementation of chromium malate in rats was better than that of chromium picolinate.(4) The present study was designed to evaluate the mechanism of chromium malate in BRL rat hepatic cells with insulin resistance. The results indicated that chromium malate can significantly increase Glut4, phosphor-AMPKβ1 and Akt levels and Glut4、AMPKa2 and Akt2 mRNA levels. Also, the Irs-1、PPARγ、 PI3K and p38-MAPK mRNA levels of chromium malate group were significantly higher than those of the model, chromium picolinate and chromium trichloride groups. Chromium malate contributes to glucose transport and increase insulin sensitivity in order to improved glucose transport and insulin resistance in T2D.(5) The present study was designed to identify the 90-day oral toxicity, reproductive toxicity, glycometabolism, learning and memory ability and related enzymes of chromium malate in SD rats. The results showed that no pathological change nor toxicity were observed at doses of 10.0、15.0 and 20.0 μg Cr/kg bm. The pregnancy and birth indices of female rats in chromium malate groups showed no significant change compared to the control and chromium picolinate groups. The viability index on day 4 p.p. and viability index on day 21 p.p. of fetal rats had no significant change when compared with the control and chromium picolinate groups. The glycometabolism, learning and memory ability and related enzyme in chromium malate groups had no significant change, compared with the normal control and chromium picolinate groups. The results of this study suggest that chromium malate is safe for human consumption at the range of effective dose.(6) The present study was designed to identify the chronic toxicity, glycometabolism, learning and memory ability and related enzymes of chromium malate in SD rats. The results showed that no pathological and toxic changes were observed at a dose of 10.0、15.0 and 20.0μg Cr/kg bm. Glycometabolism and related enzymes had no significant change compared with the control and chromium picolinate groups. Chromium malate can significantly improve lipid metabolism, learning and memory ability and related enzymes in male rats. Therefore, it can be concluded that further studies on chromium malate as an anti-diabetic functional food and nutritional supplement, is needed. |
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